Tetramethylpyrazine Nitrone Improved Motor Deficits and Alleviated Dystrophic Muscle Pathology in the <i>mdx</i>Mouse Model of Duchenne Muscular Dystrophy  

作　　者：Fengjiao Wang Jing Wen Guiliang Zhang Zheng Liu Haijing Zhong Gaoxiao Zhang Yewei Sun Pei Yu Yuqiang Wang Zaijun Zhang Fengjiao Wang;Jing Wen;Guiliang Zhang;Zheng Liu;Haijing Zhong;Gaoxiao Zhang;Yewei Sun;Pei Yu;Yuqiang Wang;Zaijun Zhang(Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China;International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou, China;School of Stomatology and Medicine & Foshan Stomatology Hospital, Foshan University, Foshan, China;Foshan Magpie Pharmaceuticals Co., LTD., Foshan, China)

机构地区：[1]Institute of New Drug Research, Jinan University College of Pharmacy, Guangzhou, China [2]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education, Jinan University College of Pharmacy, Guangzhou, China [3]School of Stomatology and Medicine & Foshan Stomatology Hospital, Foshan University, Foshan, China [4]Foshan Magpie Pharmaceuticals Co., LTD., Foshan, China

出　　处：《Journal of Biosciences and Medicines》2020年第8期56-66,共11页生物科学与医学（英文）

摘　　要：Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle structure and function. Skeletal muscle fibrosis is one of the pathological features of DMD. Tetramethylpyrazine (2,3,5,6-tetramethylpyrazine, TMP) has been demonstrated to reduce heart and liver fibrosis. Meanwhile, previous studies showed that Tetramethylpyrazine nitrone (TBN), a nitrone derivative of TMP, has promising therapeutic effects in several neurodegenerative models and is more potent than TMP. In this study, we investigated the potential effect of TBN on the <em>mdx</em> mouse model of DMD. Eight-week-old <em>mdx</em> mice were administered with TBN (30 mg/kg) intragastrically twice daily, with deflazacort (1 mg/kg) once a day as a positive control, for a total of 24 weeks. Behavioral tests including pole-climbing open-field test were monitored every 4 weeks. Histopathological assessment was conducted in the gastrocnemius and diaphragm muscles. The effects of TBN on protein levels of dysferlin were measured by immunohistochemistry. TBN significantly reduced the climbing time in pole test and increased the total distance moved in an open-field test of <em>mdx</em> mice. TBN attenuated fibrosis in the gastrocnemius and diaphragmatic muscles. In addition, TBN protected gastrocnemius muscle fibers via increasing expression of the dysferlin in <em>mdx </em>mice. In conclusion, this study demonstrated that TBN could improve the motor deficits and muscle pathology of <em>mdx</em> mouse, and it is worth further exploring the mechanism of action of TBN for DMD treatment.Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive neuromuscular disorder caused by mutations in the dystrophin encoding gene, with the characteristics of a severe and progressive destruction of muscle structure and function. Skeletal muscle fibrosis is one of the pathological features of DMD. Tetramethylpyrazine (2,3,5,6-tetramethylpyrazine, TMP) has been demonstrated to reduce heart and liver fibrosis. Meanwhile, previous studies showed that Tetramethylpyrazine nitrone (TBN), a nitrone derivative of TMP, has promising therapeutic effects in several neurodegenerative models and is more potent than TMP. In this study, we investigated the potential effect of TBN on the <em>mdx</em> mouse model of DMD. Eight-week-old <em>mdx</em> mice were administered with TBN (30 mg/kg) intragastrically twice daily, with deflazacort (1 mg/kg) once a day as a positive control, for a total of 24 weeks. Behavioral tests including pole-climbing open-field test were monitored every 4 weeks. Histopathological assessment was conducted in the gastrocnemius and diaphragm muscles. The effects of TBN on protein levels of dysferlin were measured by immunohistochemistry. TBN significantly reduced the climbing time in pole test and increased the total distance moved in an open-field test of <em>mdx</em> mice. TBN attenuated fibrosis in the gastrocnemius and diaphragmatic muscles. In addition, TBN protected gastrocnemius muscle fibers via increasing expression of the dysferlin in <em>mdx </em>mice. In conclusion, this study demonstrated that TBN could improve the motor deficits and muscle pathology of <em>mdx</em> mouse, and it is worth further exploring the mechanism of action of TBN for DMD treatment.

关 键 词：Duchenne Muscular Dystrophy Fibrosis DYSFERLIN TBN mdx Mouse 

分 类 号：O62[理学—有机化学]